The invention relates to methods for administering biologically active substances, and biodegradable compositions for administering these substances.
The rapid advances in the fields of genetic engineering and biotechnology have led to the development of an increasing number of proteins and peptides that are useful as pharmaceutical agents. The development of methods for administering these new pharmaceutical agents is thus gaining increasing importance. In particular, the local or systemic administration of biologically active substances, such as proteins, is a current concern.
The delivery of proteins can be complicated, as proteins will degrade in many of the carriers that have traditionally been used for the administration of small molecules. In many cases, the active forms of proteins are difficult to formulate in biodegradable polymers. Synthetic materials, such as biodegradable hydrogels, can be used to deliver proteins. In many methods, however, the delivery of the protein to the systemic and local circulation is relatively rapid, and is determined primarily by the rate of dissolution of the protein particles. These methods can be of limited utility, as drug release can occur in an initial xe2x80x9cburstxe2x80x9d rather than at a sustained, controlled rate.
In a first aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a polymerizable monovinyl monomer.
In a second aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a water soluble polymerizable monovinyl monomer.
In a third aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a vinyl pyrrolidone monomer. The invention also features compositions formed by these methods.
In a fourth aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the articles release at least 80% of the active substance at a time 2.5 times greater than t50.
In a fifth aspect, the invention features a method for delivering a biologically active substance including the steps of: (a) combining the active substance with a macromer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the articles release a therapeutic dose of the active substance for a period of time at least 2.5 times greater than t50.
In a sixth aspect, the invention features a composition for delivering a biologically active substance, the composition including particles including a hydrogel and a biologically active substance, where the release kinetics of the particles are independent of particle size, where the particles have a mass mean diameter of about 50 nm to about 1 mm.
In a seventh aspect, the invention features a method for making articles for the controlled release of a biologically active substance including the steps of: (a) combining the active substance with a biodegradable, polymerizable macromer, the macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region, in the presence of an initiator; (b) polymerizing the macromer in the absence of light to form a hydrogel and to incorporate the active substance into the hydrogel; and (c) forming the hydrogel into articles capable of controlled release of the active substance. The initiator may be a radical initiator or an ionic initiator.
In an eighth aspect, the invention features a method for making a polymerized hydrogel, the method including the steps of: (a) combining a hydrophobic, water insoluble macromer, an initiator, and water; (b) allowing the macromer to swell; (c) mixing the macromer to form a homogenous mixture; and (d) polymerizing the macromer to form a hydrogel. Preferably, the method further includes adding a biologically active substance to the mixture before step (d).
In a ninth aspect, the invention features a method for making a polymerized hydrogel including the steps of: (a) combining a hydrophilic macromer and a hydrophobic, water insoluble macromer; (b) heating and stirring the combination formed in step (a) to form a homogenous mixture; (c) cooling the mixture to room temperature (d) adding water and an initiator to the mixture and allowing the mixture to swell; and (e) polymerizing the macromer to form a hydrogel. Preferably, the method further includes adding a biologically active substance to the mixture before step (e).
In a tenth aspect, the invention features a method for delivering a protein including the steps of: (a) combining the protein with a polymerizable hydrophilic polymer; (b) forming a mixture of the combination formed in step (a); (c) polymerizing the mixture to form articles; and (d) administering the articles, or a portion thereof, to a mammal, where the protein remains intact, and where at least 70% of the protein is released from the articles.
In an eleventh aspect, the invention features a method for delivering a biologically active substance, the method including the steps of: (a) combining the active substance with a biodegradable, polymerizable macromer in an aqueous solution, in the presence of a free radical initiator; (b) dispersing the solution to form fine droplets including the macromer and the biologically active substance; (c) polymerizing the macromer in the droplets, thereby forming hydrogel particles having the biologically active substance incorporated therein, where the particles are capable of controlled release of the biologically active agent; and (d) administering the articles, or a portion thereof, to a mammal, where step (c) takes place in the absence of a vinyl pyrrolidone monomer. Preferably, at least 80% of the particles have a particle size of smaller than about 5 xcexcm.
In a twelfth aspect, the invention features a composition including a biologically active substance enclosed within a biodegradable, polymerizable macromer, the macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region, where the composition contains at least 5% by weight of the active substance.
In a thirteenth aspect, the invention features an insoluble macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region.
In a fourteenth aspect, the invention features composition for the sustained delivery of a protein, where the composition includes an insoluble macromer with at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region.
In a fifteenth aspect, the invention features a macromer including at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region, where the degradable region consists essentially of poly(trimethylene carbonate).
In a sixteenth aspect, the invention features a composition for the subcutaneous administration of LHRH, where the composition includes a core of poly(ethylene glycol) having a molecular weight of about 1000 daltons, and a degradable region consisting of poly(caprolactone), where the composition is capable of delivering a therapeutic dose of LHRH for more than 30 days.
In a seventeenth aspect, the invention features a composition comprising glucagon-like peptide-1 and a macromer that includes at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer polymerization, where the polymerizable end groups are separated by at least one degradable region.
In an eighteenth aspect, the invention features a hydrogel composition for the sustained release of a biologically active substance, where the composition includes particles having a tap density of less than 0.4 g/cm3, where at least 50% of the particles have a mass mean diameter of less than about 5 xcexcm, and where the composition is formulated for pulmonary administration.
In a nineteenth aspect, the invention features a composition for the sustained release of a biologically active substance, where the composition includes particles hating a tap density of more than 0.4 g/cm3.
In the aspects of the invention described above, preferred embodiments are as follows. The time at which 10% of the releasable active substance is released is greater than {fraction (1/10)} of t50. Articles and macromer compositions include at least 2.5% active substance by weight, and preferably includes at least 5%, 10%, 25%, or 40% active substance by weight. Macromers include: (a) a water soluble region forming a central core; (b) at least two degradable regions attached to the core; and (c) at least two polymerizable end groups, where the polymerizable end groups are attached to the degradable regions.
The water soluble region includes a polymer selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline ), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof. The water soluble region may include at least 2 arms.
The degradable region includes a polymer selected from the group consisting of poly(xcex1-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates) and poly(phosphoesters). For example, the degradable region may include poly(trimethylene carbonate) or poly(caprolactone). Alternatively, the degradable region may contain a poly(xcex1-hydroxy acid) selected from the group consisting of poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). The degradable region may alternatively include a poly(lactone) selected from the group consisting of poly(xcex5-caprolactone), poly(xcex4-valerolactone), and poly(xcex3-butyrolactone). The degradable region may include a copolymer of at least two different monomers or a blend of at least two different monomers.
The polymerizable end groups contain a carbon-carbon double bond capable of polymerizing the macromers.
The articles are administered to the lung of the mammal. Alternatively, the articles are administered intravenously, subcutaneously, intramuscularly, orally, or nasally. Preferably, the articles are administered to humans, and the biologically active substance is preferably a protein.
By xe2x80x9ctherapeutic dose,xe2x80x9d when referreing to a biologically active substance, is meant a plasma level between the minimum effective level and the toxic level.
By xe2x80x9crelease kineticsxe2x80x9d is meant the rate at which a drug is released from its device/dosage form.
By xe2x80x9cmacromerxe2x80x9d is meant a polymer with three components: (1) a biocompatible, water soluble region; (2) a biodegradable/hydrolyzable region, and (3) at least two polymerizable regions.
By xe2x80x9cintact,xe2x80x9d when used in the context of a protein or peptide, is meant that the protein or peptide is in its biologically active form, and is not degraded or aggregated.
By xe2x80x9cinsoluble in waterxe2x80x9d or xe2x80x9cwater insolublexe2x80x9d is meant that the solubility of a compound is less than 1 g/100 ml in aqueous solution or in aqueous solution containing up to 5% of an organic solvent, such as dimethylsulfoxide.
The methods and compositions of the invention provide for the controlled release of relatively large quantities of biologically active agents, such as proteins. The macromers used to deliver the proteins both protect the proteins from degrading and also allow for adjusting the release rate of the proteins. Proteins can be delivered over a period of hours, or over a period of months. In addition, the methods and compositions of the invention provide a relatively constant dose of the active substance, rather than a burst of the substance.